6-Substituted penicillanic acid and derivatives thereof

ABSTRACT

Disclosed herein are penicillanic acids and derivatives thereof which are substituted in the 6-position, processes for preparing such compounds and the utility thereof. The compounds of the invention have been found to be useful as antibacterial agents.

This application is a divisional of Ser. No. 276,548 filed July 31, 1972which in turn is a continuation-in-part of Ser. No. 108,952 filed Jan.22, 1971, now abandoned.

SUMMARY OF INVENTION

This invention relates to 6-substituted-6-aminopenicillanic acid havingthe following Formula I: ##STR1## wherein R³ is alkyl, aralkyl, alkylenealkyl, cycloalkyl or cycloalkylene and R⁴ is hydrogen, lower alkyl,aralkyl, substituted alkyl, substituted aralkyl, trimethylsilyl, orcation. These compounds have been found to be useful as antibacterialagents and as intermediates in the preparation of6-acylamino-6-substituted penicillanic acids and pharmaceuticallyacceptable salts thereof.

DESCRIPTION OF INVENTION

This invention relates to novel 6-substituted-6-amino penicillanic acidand derivatives thereof which are active as antibacterial agents and arevaluable intermediates utilized in the preparation of the acylatedderivatives. The 6-substituted-6-amino penicillanic acids and salts ofthis invention also possess antibacterial activity which is enhanced byacylation of the 6-amino group. In Formula I above the termpharmaceutically acceptable cation means an alkali metal (e.g., sodiumand potassium), an alkaline earth metal (e.g., calcium and magnesium),ammonium, or an amine, such as a lower alkyl amine (e.g., methylamine),a di(lower alkyl)amine (e.g., diethylamine), a phenyl-lower alkylamine(e.g., benzylamine), a di(phenyl-lower alkyl)-amine (e.g.,dibenzylamine), or an alkylenediamine(e.g.,N,N'-dibenzylethylenediamine), or the like.

Compounds of Formula I are prepared by reaction a Schiff's base of6-aminopenicillanic acid of Formula II: ##STR2## wherein R⁹ is phenyl,X-substituted phenyl, lower alkyl or aralkyl (e.g., benzyl orphenethyl), wherein X is halogen (e.g., chloro, bromo), alkoxy, hydroxy,nitro, amine, or lower alkyl; with a compound having the Formula III:

    R.sup.3 - L                                                III

wherein L is a leaving group such as halogen (e.g., chloro-, bromo-, andso forth), sulfonate, sulfate, methylsulfonyloxy, p-toluenesulfonyloxy,and R³ is as defined herein.

This reaction is conducted in the presence of a base, such astriphenylmethyl sodium, sodium hydride, sodium hydroxide, potassiumt-butoxide, sodium methoxide, etc.

Compounds of Formula III that may be utilized in the practice of theinvention include methyl sulfate, ethyl sulfate, methylp-toluenesulfonate, propyliodide, allylchloride, benzylchloride,hexylchloride, 1,2-dichloropropene-2, butylbromide, methyl iodide and soforth.

It is to be understood that the term lower alkyl and lower alkoxy in theformulae of the instant invention include straight and branched chainradicals of from 1 to about 8 carbons such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, t-butyl, amyl, methoxy, ethoxy, propoxy,isopropoxy, and the like. Further, it will be appreciated that certainof the compounds of this invention exist in different optically activeforms. The various stereoisomeric forms as well as the racemic compoundsare within the scope of this invention.

The term aryl is intended to include phenyl, α- and β-naphthyl, Inaddition, the term aryl is intended to encompass mono anddisubstituted-phenyl, or α- and β-naphthyl groups wherein saidsubstituents are halogen, hydroxy, amino, nitro and alkyl.

The term heterocyclyl, while intended to encompass the entire class,more specifically is intended to encompass the thiophene, isoxazole,oxadiazole, thiadiazole, pyridine, pyrazene, morpholine, quinoline,isoquinoline, tetrazole, furan, pyrrole and indole. The ring systems maybe at various hydrogenated states, such as dihydrofuran andtetrahydroduran. In addition, the point of linkage may be at any of thepossible ring positions and the ring systems may carry additionalsubstituents such as alkyl, alkoxy, amino, nitro, halogen, etc.

Suitable compounds of Formula II include any Schiff's base of 6-APA (ora protected form thereof). When using this process, the preferredSchiff's bases are those formed with aldehydes which do not interferewith the alkylation reaction. Thus, although any of the Schiff's basesof 6-APA disclosed in U.S. Pat. No. 3,288,800 can be used, the preferredare those of the formula:

    RCHO

wherein R is phenyl, p-methoxyphenyl, m-nitrophenyl, halophenyl (e.g.,p-chlorophenyl, m-fluorophenyl and o-bromophenyl), (lower alkoxy)phenyl(e.g., o-methoxyphenyl), carbo(lower alkoxy)phenyl (e.g.,p-carbomethoxyphenyl, o-carboethoxyphenyl, p-carbohexyloxyphenyl, andm-carbobutoxyphenyl), o-n-propoxyphenyl, and p-n-hexyloxyphenyl),di(lower alkyl) aminophenyl [e.g., p-dimethylaminophenyl,o-diethylaminophenyl, p-(N-n-butyl-N-methylamino)phenyl, andm-di-n-pentylaminophenyl], naphthyl. The reaction in forming compoundsof Formula II is preferably conducted in an inert organic solvent forthe Schiff's base reactant, such as methylene chloride, benzene,dimethoxyethane, dioxane and chloroform.

Compounds of the Formula II can be used in either their salt form or inthe form of an ester. Suitable salt forms include those with alkalimetals (e.g., sodium and potassium), alkaline earth metals (e.g.,calcium). Suitable esters include those formed with lower alkanols(e.g., methanol, ethanol and tert.-butanol), cycloalkanols (e.g.,cyclohexanol and cyclopentanol), carbocyclic aryl alcohols (e.g. phenoland 2-naphthol), carbocyclic ar(lower alkanols), (e.g., benzyl alcohol,benzhydrol, 1-naphthylmethyl alcohol and 2-phenylethanol),trimethylsilyl, lower alkanoyl(lower alkanols) (e.g., hydroxyacetone andpivaloylmethanol), carbocyclic aroyl(lower alkanols) (e.g.,benzoylmethanol, 2-benzoylethanol and 2-naphthylcarbonylmethanol),cycloalkylcarbonyl(lower alkanols) (e.g.,hydroxymethylcyclohexylketone), lower alkanoyloxy (lower alkanols)(e.g., pivaloyloxymethanol), and substituted derivatives of any of theabove, such as lower alkyl (e.g., methyl and ethyl), lower alkoxy (e.g.,methoxy and butoxy), halo (e.g., chloro, fluoro and bromo), and nitroderivatives, as exemplified by 2,2,2-trichloroethanol, 2-bromoethanol,p-nitrophenol, p-methoxyphenol, p-methoxybenzyl alcohol,p,p'-dimethoxybenzhydrol, 2-dimethylamino ethanol,p-nitrobenzoylmethanol and p-methoxybenzoylmethanol. In addition thefree acid may be utilized with the reaction being carried out withexcess of base thus forming the salt in situ.

The reaction of compound II with Compound III yields a compound ofFormula IV: ##STR3## which can then be converted to compounds of FormulaI by hydrolysis in the presence of a mild aqueous acid, such ashydrochloric, sulfuric, formic, trifluoroacetic and acetic acid,p-toluene-sulphonic acid to yield the 6-substituted-6-aminopenicillanicacid of Formula I.

As stated above compounds of Formula I are valuable intermediates in theformation of acylated compounds having the Formula V: ##STR4## whereinR³ and R⁴ are as defined herein and R is acyl. Acyl in this invention isdefined as:

(a) R² (CH₂)_(n) CO-- where R² is phenyl, nitrophenyl, chlorophenyl,bromophenyl, lower alkyl phenyl, lower alkoxy phenyl, cycloalkyl orthienyl, and n is 0 or an integer from 1 to 4;

(b) R⁵ CO-- where R⁵ contains from 2 to 7 carbon atoms and is alkyl,alkylthioalkyl or alkoxyalkoxyalkyl;

(c) R⁶ CO-- where R⁶ contains from 2 to 7 carbon atoms and is alkenyl,alkylthioalkenyl, alkenylthioalkyl, alkoxyalkenyl or alkenyloxyalkyl;

(d) R² X₁ (CH₂)_(n) CO-- where R² and n are as defined above and X₁ isoxygen or sulphur.

(e) R² (CH₂)_(n) S(CH₂)_(m) CH₂ CO-- where R² and n are as defined aboveand m is 0 or an integer from 1 to 4;

(f) R⁷ (CH₂)_(n) CO-- where R⁷ is carbocyclic or substituted carbocyclic(e.g., lower alkyl dihydrocyclohexyl, lower alkoxy dihydrocyclohexylsuch as 2,4-dimethyl-2,4-dihydrocyclohexyl, and2-propoxy-2,4-dihydrocyclohexyl), aryl, hetercyclyl, aryloxy, arylthio,and alkyloxy and n is an integer from 0, 1 to 4;

(g) ##STR5## where R⁷ is as defined herein, R⁸ is alkyl, amino, ureido,carboxy, sulfonyl, phosphonyl, hydrogen, hydroxy, chloro, bromo, oriodo; p is an integer from 0, 1 to 3, and

(h) ##STR6## where R², R⁸ and p are as defined above.

The formation of compounds of general Formula V may, for example, beeffected by one of the following methods:

(a) Reaction of the compound of general Formula I with an acid chloride,or acid anhydride, active ester, acid azide, etc. in aqueous or organicsolution.

(b) Reaction of the compound of general Formula I with a mixed anhydrideof an acid corresponding to the desired acyl group and another acid, themixed anhydride being formed by reaction of the acid corresponding tothe desired acyl group with an alkyl haloformate, if desired formed insitu; the reaction with the mixed anhydride preferably being conductedin solution in an anhydrous, inert solvent in the presence of an acidbinding agent e.g., a tertiary amine.

(c) Reaction of the compound of Formula I with the activated form of acarboxylic acid formed by reaction with carbonyl-di-imidazole ordicyclohexylcarbodiimide or similar activating agent.

The compounds of this invention have antibiotic activity againstgram-positive organisms, such as Staphylococcus aureus and Streptococcuspyrogenes. They may be used as antibacterial agents in a prophylacticmanner, e.g., in cleaning or disinfecting compositions, or otherwise tocombat infections due to organisms such as those named above, and ingeneral may be utilized in a manner similar to penicillin G and otherpenicillins. For example, a compound of Formula I may be used in variousanimal species in an amount of about 0.1 to 100 mg/kg daily, orally orparenterally, in single or two to four divided doses to treat infectionsof bacterial origin. In cleaning or disinfecting compositions, e.g., infarm or dairy equipment, a concentration of about 0.01 to 1% by weightof such compounds admixed with, suspended or dissolved in conventionalinert dry or aqueous carriers by application by washing or spraying maybe utilized.

The following examples illustrate the invention (all temperatures beingin degrees Centigrade, unless otherwise stated):

EXAMPLE 1 N-Benzylidene-6-aminopenicillanic Acid

73.8 Mmoles N-benzylidene-6-aminopenicillanic acid, t-octylamine salt isadded to 240 ml methylene chloride cooled to 0°-5° C (water bath). Afterdispersion 158.5 mmoles benzaldehyde are added, followed by the additionof an 8 ml tetrahydrofuran solution containing 76.2 mmolestrifluoroacetic acid. During the course of this addition, the reactionmixture gradually clarifies to finally form a clear, slightly yellowsolution. The reaction mixture is allowed to reach room temperature andconcentrated to one-third its volume in vacuo at a temperature notexceeding 30° C. On cooling the desired product crystallized out in 82mole %.

EXAMPLE 2 Salicylidene 6-APA

200 mg of a solution of 6-aminopenicillanic acid is neutralized with 40%sodium hydroxide to a pH of 3.5 and 2 ml of salicylaldehyde is added.The mixture is agitated one hour at room temperature and allowed tostand at 5°-10° for an additional hour. The oil which forms on thebottom is separated by decantation and centrifugation. This oil issalicylidene 6-aminopenicillanic acid.

EXAMPLES 3 - 5

By following the procedure of Example 2 and substituting in place of thesalicylaldehyde an equivalent amount of:

o-nitrobenzaldehyde,

m-chlorobenzaldehyde, and

p-methoxybenzaldehyde,

the products obtained are:

N-o-nitrobenzyledene-6-aminopenicillanic acid,

N-m-chlorobenzyledene-6-aminopenicillanic acid, and

N-p-methoxybenzyledene-6-aminopenicillanic acid.

EXAMPLE 6 Benzyl ester of N-benzylidene-6-aminopenicillanic acid

Treatment of a 0.1 molar solution of N-benzylidene-6-aminopenicillanicacid with one equivalent of phenyl diazomethane in ether (Overberger andAnselme, J. ORG. CHEM., 28, 592 [1963]; Idem, J. AM. CHEM. SOC., 86, 658[1964]) for one hour, followed by evaporation deposits the product.

EXAMPLE 7 Diphenylmethyl ester of N-benzylidene-6-aminopenicillanic acid

Substitution of one equivalent of diphenyldiazomethane for the solutionof phenyl diazomethane in Example 6 gives the desired product.

EXAMPLE 8 Trichloroethyl ester of N-benzylidene-6-aminopenicillanic acid

The Schiff base of Example 1 (10.0 g) is dissolved in 150 ml ofdichloromethane containing pyridine (5.2 g). Trichloroethanol 9.84 g isadded followed by 6.79 g dicyclohexylcarbodiimide and the mixturestirred for two hours at room temperature. Precipitation ofdicyclohexylurea occurs quickly. After two hours the precipitate isfiltered off. The filtrate is diluted with dichloromethane and washedtwice with an equal volume of water, first at pH 3.5, then at pH 7.2. Itis then washed with saturated sodium chloride, dried over anhydrousmagnesium sulfate, and stripped to dryness in vacuo. Wt. of yellow oil =15.6 g.

The product is crystallized by dissolving it in 5 ml of ether and addinghexane to the warm solution until slightly turbid upon cooling.

EXAMPLE 9 Methyl ester of N-benzylidene-6-amino penicillanic acid

By treating a dioxane solution of the product of Example 1 with excessethereal diazomethane, followed by evaporation of the solvent, thedesired product is obtained. Trituration with hexane gives a powder.

EXAMPLE 10 6-Amino-6-methyl penicillanic acid

A solution of the benzaldehyde Schiff base 0.010 mole of 6-APA ofExample 1 in 50 ml of dimethoxyethane is chilled to 0° C under nitrogen;0.020 mole of sodium hydride powder (mineral oil dispersion) is added,followed by 0.030 mole (excess) methyl iodide. The solution is rapidlystirred until hydrogen evolution is slowed or stops. Thin layerchromatography can be used to maintain disappearance of startingmaterial and formation of the desired product. The reaction mixture isdiluted with 100 ml water and the pH adjusted to 2.5 (at 0° C). Thereaction mixture is filtered and extracted with 2 portions of ether. ThepH is readjusted to 4.5, and concentrated in vacuo if necessary, toprecipitate the product.

EXAMPLE 11 N-Benzylidene-6-amino-6-methylpenicillanic acid, methyl ester

12.5 Meq. N-benzylidene-6-amino-6-penicillanic acid, methyl ester aredissolved in 2 ml dry DME under nitrogen at -5° C. Then a 20-fold excessmethyl iodide is added along with 12.5 meq. sodium hydride. The reactionmixture turns yellow after a few minutes of stirring at that lowtemperature. After 3 hours, thin layer chromatography on silica gel,showed no more starting material. The reaction mixture is diluted withchloroform, washed with water, dried over magnesium sulphate andevaporated in vacuo to give 5.05 grams of a brown oil. This wasrecrystallized from hexane-dichloromethane to give 6.6 meq.6-benzalimino-6-α-methylpenicillanic acid, methyl ester; chromatographyof the mother liquors on silica gel led to the isolation of theβ-6-methyl epimer.

EXAMPLE 12 N-Benzylidene-6-amino-6-methylpenicillanic acid benzyl ester

Substitution of 12.5 meq. of the benzyl ester of6-benzyliminopenicillanic acid acid in Example 11 for the methyl esterleads to the desired product.

EXAMPLE 13 N-Benzylidene-6-amino-6-methylpenicillanic acid benzhydrylester

By substituting 12.5 meq. of the benzhydryl ester for the methyl esterof Example 11, the desired product is obtained.

EXAMPLE 14 6-Amino-6-methylpenicillanic acid, methyl ester

5.1 Meq. 6-benzalimino-6-methylpenicillanic acid, methyl ester arehydrolyzed in a 50:50 mixture of acetone and 0.1 N aqueous hydrochloricacid for 10 minutes. The reaction mixture is then diluted with water andwashed with chloroform. The acidic layer is then basified and extractedwith chloroform. This latter chloroform layer is dried over magnesiumsulphate and evaporated to dryness in vacuo. To give 4 meq.6-amino-6-methylpenicillanic acid, methyl ester. MP 94°-95°.

EXAMPLE 15 6-Amino-6-methylpenicillanic acid, benzyl ester

Substituting 5.1 meq. of the product of Example 12 for the substrate ofExample 14, and following the procedure therein, the desired product isobtained.

EXAMPLE 16 6-Amino-6-methylpenicillanic acid, benzhydryl ester

Substituting 5.1 meq. of the product of Example 13 for the substrate ofExample 10, and following the procedure therein, the desired product isobtained.

EXAMPLE 17 6-Phenylacetamido-6-methylpenicillanic acid, methyl ester2.25 Meq. 6-amino-6-methylpenicillanic acid, methyl ester are dissolvedin 30 ml. chloroform, and cooled to ice-bath temperature under nitrogen.Then 2.25 meq. triethylamine are added followed by the addition of 2.25meq. phenylacetylchloride. The reaction is allowed to proceed for twohours at ice-bath temperatures and under nitrogen. The solution isdiluted with chloroform, washed with a solution at pH 7.2, washed withwater, dried over magnesium sulphate, and evaporated to dryness to give1.1 meq. of 6-phenylacetamido-6-methylpenicillanic acid, methyl ester asa clear oil which crystallizes on standing. EXAMPLE 186-Phenylacetamido-6-methylpenicillanic acid

(a) By hydrolysis; 1 mmole of the6-(phenylacetamido)-6-methylpenicillanic acid, methyl ester in 10 ml.95% ethanol is treated with one ml. of 1N NaOH at room temperature for 6hours with stirring; the alcohol is evaporated at reduced pressure. Theresidue is dissolved in water and pH adjusted to 7.5 if necessary. Theaqueous solution is washed with ethyl acetate, filtered and acidified topH 4 at 0° C. to precipitate the product.

(b) The product of Example 10 obtained by using methyl iodide as asolution with triethylamine in 1:1 water/acetone at 0° C is treated withone equivalent of phenylacetyl chloride, with triethylamine being addedto maintain pH at 6.5 to 7.5. When no further pH change is noted thereaction is worked up as in part a) to give the desired product.

(c) A suspension of the t-octyl amine salt (0.1 mol.) of thebenzaldehyde Schiff base of 6-APA in 100 ml of dimethoxyethane istreated with 10.8 g of trimethyl silyl chloride at 10° C for 2 hours.The reaction mix is filtered and 0.1 eq. of sodium hydride as a mineraloil dispersion is added followed immediately by 28 g of methyl iodide.After two to three hours, the reaction mix is diluted with 250 ml H₂ 0and acidified to pH 2. After 20 minutes the result is filtered and thefiltrate washed with ether. Adjusting the pH of the solution to 7 withtriethylamine gives a solution of 6-methyl-6-APA which can be acylatedwith 0.10 mol. phenylacetyl chloride as in 18b to give the product.

Similarly, by substituting an equivalent amount of phenoxyacetylchloride for the phenylacetyl chloride, one obtains6-phenoxyacetyl-6-methylpenicillanic acid.

EXAMPLE 19 6-Amino-6-benzylpenicillanic acid

6-Amino-6-benzylpenicillanic acid is prepared by using benzyl chloridein lieu of methyl iodide of Example 10.

EXAMPLE 20 N-Benzylidene-6-amino-6-benzylpenicillanic acid, methyl ester

N-Benzylidene-6-amino-6-benzylpenicillanic acid, methyl ester isprepared by the procedure of Example 11, but using an equivalent amountof benzyl chloride in place of methyl iodide.

EXAMPLE 21 6-Amino-6-benzylpenicillanic acid, methyl ester

6-Amino-6-benzylpenicillanic acid, methyl ester is prepared by using theproduct of Example 20 to replace the substrate 6-methyl compound ofExample 14.

EXAMPLE 22 6-Phenylacetamido-6-benzylpenicillanic acid, methyl ester

6-Phenylacetamido-6-benzylpenicillanic acid, methyl ester is prepared byusing the product of Example 19 for the substrate in Example 17.

EXAMPLE 23 6-Phenylacetamido-6-benzylpenicillanic acid

6-Phenylacetamido-6-benzylpenicillanic acid is prepared by the Exampleprocedures of 18, substituting the corresponding 6-benzyl compound forthe 6-methyl compounds.

Similarly, by also substituting an equivalent amount of phenoxyacetylchloride for the phenylacetyl chloride, one obtains6-phenoxyacetyl-6-benzylpenicillanic acid.

EXAMPLES 24 - 46 6-Acylamino-6-methylpenicillanic acids

By following the procedure of Example 18b and substituting an equivalentamount of the corresponding acid chloride of the following carboxylicacids:

α-(2-chlorophenoxy)propionic acid,

α-(4-sulfamylphenoxy)-n-butyric acid,

α-(3,4-dimethoxyphenoxy)-n-pentanoic acid,

α-(3-methylphenoxy)isovaleric acid,

α-(4-methylthiophenoxy)propionic acid,

α-(4-dimethylaminophenoxy)-n-hexanoic acid,

α-(2-methoxyphenoxy)-n-decanoic acid,

α-(2,4-dichlorophenoxy)phenylacetic acid,

α-(2-nitrophenoxy)-β-phenylpropionic acid,

α-(2-acetamidophenoxy)-γ-phenylbutyric acid,

α-(2,4-dimethylphenoxy)-n-butyric acid,

α-(4-isopropylphenoxy)propionic acid,

α-(3-bromophenoxy)-n-butyric acid,

α-(2-iodophenoxy)phenylacetic acid,

α-(2-diethylaminophenoxy)isovaleric acid,

α-(3,5-dichlorophenoxy)isohexanoic acid,

α-(4-cyclohexylphenoxy)propionic acid,

α-phenoxy-isovaleric acid,

α-phenoxy-n-decanoic acid,

α-phenoxy- γ -phenylbutyric acid,

α-(2-benzylphenoxy)-n-butyric acid,

α-(2-trifluoromethylphenoxy)propionic acid, and

α-(4-fluorophenoxy)propionic acid, the products obtained are

6-[α-(2-chlorophenoxy)propionamido]-6-methylpenicillanic acid,

6-[α-(4-sulfamylphenoxy)-n-butyramido]-6-methylpenicillanic acid,

6-[α-(3,4-dimethoxyphenoxy)-n-pentanoamido]-6-methylpenicillanic acid,

6-[α-(3-methylphenoxy)isovaleramido]-6-methylpenicillanic acid,

6-[α-(4-methylthiophenoxy)propionamido]-6-methylpenicillanic acid,

6-[α-(4-dimethylaminophenoxy)-n-hexanoamido]-6-methylpenicillanic acid,

6-[α-(2-methoxyphenoxy)-n-decanoamido]-6-methylpenicillanic acid,

6-[α-(2,4-dichlorophenoxy)phenylacetamido]-6-methylpenicillanic acid,

6-[α-(2-nitrophenoxy)-β-phenylpropionamido]-6-methylpenicillanic acid,

6-[α-(2-acetamidophenoxy)- γ -phenylbutyramido]-6-methylpenicillanicacid,

6-[α-(2,4-dimethylphenoxy)-n-butyramido]-6-methylpenicillanic acid,

6-[α-(4-isopropylphenoxy)propionamido]-6-methylpenicillanic acid,

6-[α-(3-bromophenoxy)-n-butyramido]-6-methylpenicillanic acid,

6-[α-(2-iodophenoxy)phenylacetamido]-6-methylpenicillanic acid,

6-[α-(2-diethylaminophenoxy)isovaleramido]-6-methylpenicillanic acid,

6-[α-(3,5-dichlorophenoxy)isohexanoamido]-6-methylpenicillanic acid,

6-[α-(4-cyclohexylphenoxy)propionamido]-6-methylpenicillanic acid,

6-[α-phenoxy-isovaleramido]-6-methylpenicillanic acid,

6-[α-phenoxy-n-decanoamido]-6-methylpenicillanic acid,

6-[α-phenoxy- γ -phenylbutyramido]-6-methylpenicillanic acid,

6-[α-(2-benzylphenoxy)-n-butyramido]-6-methylpenicillanic acid,

6-[α-(2-trifluoromethylphenoxy)propionamido]-6-methylpenicillanic acid,and

6-[α-(4-fluorophenoxy)propionamido]-6-methylpenicillanic acid,respectively.

EXAMPLES 48 - 76

By following the procedure of Example 18b and substituting an equivalentamount of the corresponding acid chloride of the following carboxylicacids:

α-phenylthiopropionic acid,

α-paranitrophenylthiopropionic acid,

α-parachlorophenylthiopropionic acid,

α-phenylthiobutyric acid,

α-phenylthiocaproic acid,

α-phenylthioisovaleric acid,

α-(4-t-butylphenylthio)propionic acid,

α-ortho-tolylthiopropionic acid,

α-ortho-nitrophenylthiopropionic acid,

α-parachlorophenylthiobutyric acid,

α-(3,4,5-trichlorophenylthio)propionic acid,

α-(3-trifluoromethylphenylthio)butyric acid,

α-parabromophenylthioisovaleric acid,

α-paraphenylphenylthiopropionic acid,

α-(4-methoxyphenylthio)caproic acid,

α-(4-cyclohexylphenylthio)butyric acid,

α-phenylthio-α-cyclohexylacetic acid,

α-phenylthio-α-cyclopentylacetic acid,

α-(2,4-dichlorophenylthio)caproic acid,

α-(2,4-diisoamylphenylthio)propionic acid,

α-(4-benzylphenylthio)propionic acid,

α-(4-sulfamylphenylthio)butyric acid,

α-(2-allyloxyphenylthio)propionic acid,

α-(4-allylphenylthio)isovaleric acid,

α-(4-dimethylaminophenylthio)propionic acid,

α-(2,5-dichlorophenylthio)butyric acid,

α-(2-iodophenylthio)propionic acid,

α-(2-acetamidophenylthio)propionic acid,

α-(4-diethylaminophenylthio)propionic acid, and

α-(3-fluorophenylthio)butyric acid, the products obtained are

6-(α-phenylthiopropionamido)-6-methylpenicillanic acid,

6-(α-paranitrophenylthiopropionamido)-6-methylpenicillanic acid,

6-(α-parachlorophenylthiopropionamido)-6-methylpenicillanic acid,

6-(α-phenylthiobutyramido)-6-methylpenicillanic acid,

6-(α-phenylthiocaproamido)-6-methylpenicillanic acid,

6-(α-phenylthioisovaleramido)-6-methylpenicillanic acid,

6-[α-(4-t-butylphenylthio)propionamido]-6-methylpenicillanic acid,

6-[α-ortho-tolylthiopropionamido]-6-methylpenicillanic acid,

6-(α-ortho-nitrophenylthiopropionamido)-6-methylpenicillanic acid,

6-(α-parachlorophenylthiobutyramido)-6-methylpenicillanic acid,

6-[α-(3,4,5-trichlorophenylthio)propionamido]-6-methylpenicillanic acid,

6-[α-(3-trifluoromethylphenylthio)butyramido]-6-methylpenicillanic acid,

6-(α-parabromophenylthioisovaleramido)-6-methylpenicillanic acid,

6-(α-paraphenylphenylthiopropionamido)-6-methylpenicillanic acid,

6-[α-(4-methoxyphenylthio)caproamido]-6-methylpenicillanic acid,

6-[α-(4-cyclohexylphenylthio)butyramido]-6-methylpenicillanic acid,

6-(α-phenylthio-α-cyclohexylacetamido)-6-methylpenicillanic acid,

6-(α-phenylthio-α-cyclopentylacetamido)-6-methylpenicillanic acid,

6-[α-(2,4-dichlorophenylthio)caproamido]-6-methylpenicillanic acid,

6-[α-(2,4-diisoamylphenylthio)propionamido]-6-methylpenicillanic acid,

6-[α-(4-benzylphenylthio)propionamido]-6-methylpenicillanic acid,

6-[α-(4-sulfamylphenylthio)butyramido]-6-methylpenicillanic acid,

6-[α-(2-allyloxyphenylthio)propionamido]-6-methylpenicillanic acid,

6-[α-(4-allylphenylthio)isovaleramido]-6-methylpenicillanic acid,

6-[α-(4-dimethylaminophenylthio)propionamido]-6-methylpenicillanic acid,

6-[α-(2,5-dichlorophenylthio)butyramido]-6-methylpenicillanic acid,

6-[α-(2-iodophenylthio)propionamido]-6-methylpenicillanic acid,

6-[α-(2-acetamidophenylthio)propionamido]-6-methylpenicillanic acid,

6-[α-(4-diethylaminophenylthio)propionamido]-6-methylpenicillanic acid,and

6-[α-(3-fluorophenylthio)butyramido]-6-methylpenicillanic acid,respectively.

EXAMPLES 79 - 90

By following the procedure of Example 18b and substituting an equivalentamount of the corresponding acid chloride of the following carboxylicacids

D,l-α-amino-(3-thienyl)acetic acid,

α-amino-(5-ethyl-2-thienyl)acetic acid,

α-amino-(5-methyl-2-thienyl)acetic acid,

α-amino-(5-t-butyl-2-thienyl)acetic acid,

α-amino-(2,5-dimethyl-3-thienyl)acetic acid,

α-amino-(5-chloro-2-thienyl)acetic acid,

α-amino-(5-bromo-2-thienyl)acetic acid,

α-amino-(5-phenyl-3-chloro-2-thienyl)acetic acid,

α-amino-3,5-dimethyl-2-thienyl)acetic acid,

α-amino-(5-cyclohexyl-2-thienyl)acetic acid,

α-amino-(5-diethylamino-2-thienyl)acetic acid,

α-amino-(4-methylsulfonyl-2-thienyl)acetic acid,

α-amino-(3-ethylthio-2-thienyl)acetic acid, and

α-amino-(4-cycloheptyloxy-2-thienyl)acetic acid, the products obtainedare

D,l-6-[α-amino-(3-thienyl)acetamido]-6-methylpenicillanic acid,

6-[α-amino-(5-ethyl-2-thienyl)acetamido]-6-methylpenicillanic acid,

6-[α-amino-(5-methyl-2-thienyl)acetamido]-6-methylpenicillanic acid,

6-[α-amino-(5-t-butyl)-2-thienyl)acetamido]-6-methylpenicillanic acid,

6-[α-amino-(2,5-dimethyl-3-thienyl)acetamido]-6-methylpenicillanic acid,

6-[α-amino-(5-chloro-2-thienyl)acetamido]-6-methylpenicillanic acid,

6-[α-amino-(5-bromo-2-thienyl)acetamido]-6-methylpenicillanic acid,

6-[α-amino-(5-phenyl-3-chloro-2-thienyl)acetamido]-6-methylpenicillanicacid,

6-[α-amino-(3,5-dimethyl-2-thienyl)acetamido]-6-methylpenicillanic acid,

6-[α-amino-(5-cyclohexyl-2-thienyl)acetamido]-6-methylpenicillanic acid,

6-[α-amino-(5-diethylamino-2-thienyl)acetamido]-6-methylpenicillanicacid,

6-[α-amino-(4-methylsulfonyl-2-thienyl)acetamido]-6-methylpenicillanicacid,

6-[α-amino-(3-ethylthio-2-thienyl)acetamido]-6-methylpenicillanic acid,and

6-[α-amino-(4-cycloheptyloxy-2-thienyl)acetamido]-6-methylpenicillanicacid, respectively.

EXAMPLES 94 - 113

By following the procedure of Example 18b and substituting an equivalentamount of the corresponding acid chloride of the following carboxylicacids

α-amino-p-chlorophenylacetic acid,

α-amino-p-methoxyphenylacetic acid,

D-(-)-α-aminophenylacetic acid,

α-amino-4-diethylaminophenylacetic acid,

α-amino-4-trifluoromethylphenylacetic acid,

α-amino-2,4-dibromophenylacetic acid,

α-amino-2-nitrophenylacetic acid,

α-amino-3-methylphenylacetic acid,

α-amino-4-sulfamylphenylacetic acid,

α-amino-2-iodophenylacetic acid,

α-amino-4-t-butylphenylacetic acid,

α-amino-2-acetamidophenylacetic acid,

α-amino-3-nitrophenylacetic acid,

α-amino-3,4-dimethoxyphenylacetic acid,

α-amino-4-dimethylaminophenylacetic acid,

α-amino-2,4-dichlorophenylacetic acid,

α-amino-4-isopropylphenylacetic acid,

α-amino-3-bromophenylacetic acid,

α-amino-3-iodophenylacetic acid,

α-amino-2-diethylaminophenylacetic acid,

α-amino-2-trifluoromethylphenylacetic acid,

α-amino-4-fluorophenylacetic acid, and

α-amino-3,4,5-trifluoromethylphenylacetic acid, the products obtainedare 6-(α-amino-p-chlorophenylacetamido)-6-methylpenicillanic acid,

6-(α-amino-p-methoxyphenylacetamido)-6-methylpenicillanic acid,

6-[D-(-)-α-aminophenylacetamido]-6-methylpenicillanic acid,

6-(α-amino-4-diethylaminophenylacetamido)-6-methylpenicillanic acid,

6-(α-amino-4-trifluoromethylphenylacetamido)-6-methylpenicillanic acid,

6-(α-amino-2,4-dibromophenylacetamido)-6-methylpenicillanic acid,

6-(α-amino-2-nitrophenylacetamido)-6-methylpenicillanic acid,6-(α-amino-3-methylphenylacetamido)-6-methylpenicillanic acid,

6-(α-amino-4-sulfamylphenylacetamido)-6-methylpenicillanic acid,

6-(α-amino-2-iodophenylacetamido)-6-methylpenicillanic acid,

6-(α-amino-4-t-butylphenylacetamido)-6-methylpenicillanic acid,

6-(α-amino-2-acetamidophenylacetamido)-6-methylpenicillanic acid,

6-(α-amino-3-nitrophenylacetamido)-6-methylpenicillanic acid,

6-(α-amino-3,4-dimethoxyphenylacetamido)-6-methylpenicillanic acid,

6-(α-amino-4-dimethylaminophenylacetamido)-6-methylpenicillanic acid,

6-(α-amino-2,4-dichlorophenylacetamido)-6-methylpenicillanic acid,

6-(α-amino-4-isopropylphenylacetamido)-6-methylpenicillanic acid,

6-(α-amino-3-bromophenylacetamido)-6-methylpenicillanic acid,

6-(α-amino-3-iodophenylacetamido)-6-methylpenicillanic acid,

6-(α-amino-2-diethylaminophenylacetamido)-6-methylpenicillanic acid,

6-(α-amino-2-trifluoromethylphenylacetamido)-6-methylpenicillanic acid,

6-(α-amino-4-fluorophenylacetamido)-6-methylpenicillanic acid, and

6-(α-amino-3,4,5-trifluoromethylphenylacetamido)-6-methylpenicillanicacid, respectively.

EXAMPLES 118 - 184

By following the procedure of Example 18b and substituting an equivalentamount of the following acid chloride: benzoyl chloride

3,5-dinitrobenzoyl chloride,

2-chlorobenzoyl chloride,

2-methylbenzoyl chloride,

4-aminobenzoyl chloride,

4-nitrobenzoyl chloride,

4-hydroxybenzoyl chloride,

3,4,5-trimethoxybenzoyl chloride,

4-methylbenzoyl chloride,

4-chlorobenzoyl chloride,

3,4-dichlorobenzoyl chloride,

3-nitrobenzoyl chloride,

2,4,6-trimethoxybenzoyl chloride,

2-hydroxybenzoyl chloride,

4-ethoxybenzoyl chloride,

2,6-dimethoxybenzoyl chloride,

2,4,6-trimethylbenzoyl chloride,

2,6-dichlorobenzoyl chloride,

2,6-diethoxybenzoyl chloride,

2,6-di-n-butoxybenzoyl chloride,

2,6-dibenzyloxybenzoyl chloride,

2,3,6-trimethoxybenzoyl chloride,

2,4,6-tribromobenzoyl chloride,

2,6-di-n-propoxybenzoyl chloride,

2,6-dimethoxy-4-methylbenzoyl chloride,

4,6-diethyl-2-methoxybenzoyl chloride,

6-ethoxy-2-methoxybenzoyl chloride,

2-methylthiobenzoyl chloride,

2-benzylthiobenzoyl chloride,

2-phenoxybenzoyl chloride,

2-phenylbenzoyl chloride,

2-methoxybenzoyl chloride,

4-sulfamylbenzoyl chloride,

3,4-dimethoxybenzoyl chloride,

4-methoxybenzoyl chloride,

3-methylbenzoyl chloride,

3-dimethylaminobenzoyl chloride,

2-methoxybenzoyl chloride,

2-chloro-3,4,5-trimethoxybenzoyl chloride,

2,4-dichlorobenzoyl chloride,

2-nitrobenzoyl chloride,

4-methylaminobenzoyl chloride,

2-acetamidobenzoyl chloride,

2,4-dimethylbenzoyl chloride,

2,4,5-trimethylbenzoyl chloride,

4-isopropylbenzoyl chloride,

3-bromobenzoyl chloride,

2-iodobenzoyl chloride,

2-ethylaminobenzoyl chloride,

2,5-dihydroxybenzoyl chloride,

4-hydroxy-3-methoxybenzoyl chloride,

4-allylbenzoyl chloride,

4-allyloxybenzoyl chloride,

2-trifluoromethylbenzoyl chloride,

4-fluorobenzoyl chloride,

2-phenylthiobenzoyl chloride,

2-benzylbenzoyl chloride,

2,6-dihydroxybenzoyl chloride,

2,6-diacetoxybenzoyl chloride,

2,6-dimethylthiobenzoyl chloride,

2,4,6-trinitrobenzoyl chloride,

2,6-diacetamidobenzoyl chloride,

2,6-dibromobenzoyl chloride,

2,6-dimethylbenzoyl chloride,

2,6-diethylbenzoyl chloride,

2,6-diisopropylbenzoyl chloride,

2,6-diallyloxybenzoyl chloride,

3-bromo-2,6-dimethoxybenzoyl chloride,

4-chloro-2,6-dimethoxybenzoyl chloride,

2-chloro-6-nitrobenzoyl chloride, and

2-hydroxy-6-methoxybenzoyl chloride,

the products obtained are

6-(benzamido)-6-methylpenicillanic acid,

6-(3,5-dinitrobenzamido)-6-methylpenicillanic acid,

6-(2-chlorobenzamido)-6-methylpenicillanic acid,

6-(2-methylbenzamido)-6-methylpenicillanic acid,

6-(4-aminobenzamido)-6-methylpenicillanic acid,

6-(4-nitrobenzamido)-6-methylpenicillanic acid,

6-(4-hydroxybenzamido)-6-methylpenicillanic acid,

6-(3,4,5-trimethoxybenzamido)-6-methylpenicillanic acid,

6-(4-methylbenzamido)-6-methylpenicillanic acid,

6-(4-chlorobenzamido)-6-methylpenicillanic acid,

6-(3,4-dichlorobenzamido)-6-methylpenicillanic acid,

6-(3-nitrobenzamido)-6-methylpenicillanic acid,

6-(2,4,6-trimethoxybenzamido)-6-methylpenicillanic acid,

6-(2-hydroxybenzamido)-6-methylpenicillanic acid,

6-(4-ethoxybenzamido)-6-methylpenicillanic acid,

6-(2,6-dimethoxybenzamido)-6-methylpenicillanic acid,

6-(2,4,6-trimethylbenzamido)-6-methylpenicillanic acid,

6-(2,6-dichlorobenzamido)-6-methylpenicillanic acid,

6-(2,6-diethoxybenzamido)-6-methylpenicillanic acid,

6-(2,6-di-n-butoxybenzamido)-6-methylpenicillanic acid,

6-(2,6-dibenzyloxybenzamido)-6-methylpenicillanic acid,

6-(2,3,6-trimethoxybenzamido)-6-methylpenicillanic acid,

6-(2,4,6-tribromobenzamido)-6-methylpenicillanic acid,

6-(2,6-di-n-propoxybenzamido)-6-methylpenicillanic acid,

6-(2,6-dimethoxy-4-methylbenzamido)-6-methylpenicillanic acid,

6-(4,6-diethyl-2-methoxybenzamido)-6-methylpenicillanic acid,

6-(6-ethoxy-2-methoxybenzamido)-6-methylpenicillanic acid,

6-(2-methylthiobenzamido)-6-methylpenicillanic acid,

6-(2-benzylthiobenzamido)-6-methylpenicillanic acid,

6-(2-phenoxybenzamido)-6-methylpenicillanic acid,

6-(2-phenylbenzamido)-6-methylpenicillanic acid,

6-(2-methoxybenzamido)-6-methylpenicillanic acid,

6-(4-sulfamylbenzamido)-6-methylpenicillanic acid,

6-(3,4-dimethoxybenzamido)-6-methylpenicillanic acid,

6-(4-methoxybenzamido)-6-methylpenicillanic acid,

6-(3-methylbenzamido)-6-methylpenicillanic acid,

6-(3-dimethylaminobenzamido)-6-methylpenicillanic acid,

6-(2-methoxybenzamido)-6-methylpenicillanic acid,

6-(2-chloro-3,4,5-trimethoxybenzamido)-6-methylpenicillanic acid,

6-(2,4-dichlorobenzamido)-6-methylpenicillanic acid,

6-(2-nitrobenzamido)-6-methylpenicillanic acid,

6-(4-methylaminobenzamido)-6-methylpenicillanic acid,

6-(2-acetamidobenzamido)-6-methylpenicillanic acid,

6-(2,4-dimethylbenzamido)-6-methylpenicillanic acid,

6-(2,4,5-trimethylbenzamido)-6-methylpenicillanic acid,

6-(4-isopropylbenzamido)-6-methylpenicillanic acid,

6-(3-bromobenzamido)-6-methylpenicillanic acid,

6-(2-iodobenzamido)-6-methylpenicillanic acid,

6-(2-ethylaminobenzamido)-6-methylpenicillanic acid,

6-(2,5-dihydroxybenzamido)-6-methylpenicillanic acid,

6-(4-hydroxy-3-methoxybenzamido)-6-methylpenicillanic acid,

6-(4-allylbenzamido)-6-methylpenicillanic acid,

6-(4-allyloxybenzamido)-6-methylpenicillanic acid,

6-(2-trifluoromethylbenzamido)-6-methylpenicillanic acid,

6-(4-fluorobenzamido)-6-methylpenicillanic acid,

6-(2-phenylthiobenzamido)-6-methylpenicillanic acid,

6-(2-benzylbenzamido)-6-methylpenicillanic acid,

6-(2,6-dihydroxybenzamido)-6-methylpenicillanic acid,

6-(2,6-diacetoxybenzamido)-6-methylpenicillanic acid,

6-(2,6-dimethylthiobenzamido)-6-methylpenicillanic acid,

6-(2,4,6-trinitrobenzamido)-6-methylpenicillanic acid,

6-(2,6-diacetamidobenzamido)-6-methylpenicillanic acid,

6-(2,6-dibromobenzamido)-6-methylpenicillanic acid,

6-(2,6-dimethylbenzamido)-6-methylpenicillanic acid,

6-(2,6-diethylbenzamido)-6-methylpenicillanic acid,

6-(2,6-diisopropylbenzamido)-6-methylpenicillanic acid,

6-(2,6-diallyloxybenzamido)-6-methylpenicillanic acid,

6-(3-bromo-2,6-dimethoxybenzamido)-6-methylpenicillanic acid,

6-(4-chloro-2,6-dimethoxybenzamido)-6-methylpenicillanic acid,

6-(2-chloro-6-nitrobenzamido)-6-methylpenicillanic acid, and

6-(2-hydroxy-6-methoxybenzamido)-6-methylpenicillanic acid,respectively.

EXAMPLES 185 - 195

By following the procedure of Example 18b and substituting an equivalentamount of the following acid chloride:

(4-nitrophenyl)acetyl chloride,

(4-bromophenyl)acetyl chloride,

(4-t-butylphenyl)acetyl chloride,

(4-trifluoromethylphenyl)acetyl chloride,

(3-fluorophenyl)acetyl chloride,

(4-sulfamylphenyl)acetyl chloride,

(2-benzylphenyl)acetyl chloride,

(3-methoxyphenyl)acetyl chloride,

(2-iodophenyl)acetyl chloride,

(3-diethylaminophenyl)acetyl chloride, and

(2,4-diisoamylphenyl)acetyl chloride, the products obtained are

6-[α-(4-nitrophenyl)acetamido]-6-methylpenicillanic acid,

6-[α-(4-bromophenyl)acetamido]-6-methylpenicillanic acid,

6-[α-(4-t-butylphenyl)acetamido]-6-methylpenicillanic acid,

6-[α-(4-trifluoromethylphenyl)acetamido]-6-methylpenicillanic acid,

6-[α-(3-fluorophenyl)acetamido]-6-methylpenicillanic acid,

6-[α-(4-sulfamylphenyl)acetamido]-6-methylpenicillanic acid,

6-[α-(2-benzylphenyl)acetamido]-6-methylpenicillanic acid,

6-[α-(3-methoxyphenyl)acetamido]-6-methylpenicillanic acid,

6-[α-(2-iodophenyl)acetamido]-6-methylpenicillanic acid,

6-[α-(3-diethylaminophenyl)acetamido]-6-methylpenicillanic acid, and

6-[α-(2,4-diisoamylphenyl)acetamido]-6-methylpenicillanic acid,respectively.

EXAMPLES 196 - 243

By following the procedure of Example 18b and substituting an equivalentamount of the following acid chloride:

3-m-chlorophenyl-5-methyl-4-isoxazole-4-carbonyl chloride,

3-(2,4-dichlorophenyl)-5-methyl-4-isoxazole-4-carbonyl chloride,

3-(3,4-dichlorophenyl)-5-methyl-4-isoxazole-4-carbonyl chloride,

3-p-tolyl-5-methyl-4-isoxazole-4-carbonyl chloride,

3-o-nitrophenyl-5-methyl-4-isoxazole-4-carbonyl chloride,

3-m-nitrophenyl-5-methyl-4-isoxazole-4-carbonyl chloride,

3-p-nitrophenyl-5-methyl-4-isoxazole-4-carbonyl chloride,

3-p-bromophenyl-5-methyl-4-isoxazole-4-carbonyl chloride,

3-p-fluorophenyl-5-methyl-4-isoxazole-4-carbonyl chloride,

3-p-methylsulfonylphenyl-5-methyl-4-isoxazole-4-carbonyl chloride,

3-p-methoxyphenyl-5-methyl-4-isoxazole-4-carbonyl chloride,

3-p-trifluoromethylphenyl-5-methyl-4-isoxazole-4-carbonyl chloride,

3-o-methoxyphenyl-5-methyl-4-isoxazole-4-carbonyl chloride,

3-p-ethoxyphenyl-5-methyl-4-isoxazole-4-carbonyl chloride,

3-(3,4-dimethoxyphenyl)-5-methyl-4-isoxazole-4-carbonyl chloride,

3-p-dimethylaminophenyl-5-methyl-4-isoxazole-4-carbonyl chloride,

3-α-naphthyl-5-methyl-4-isoxazole-4-carbonyl chloride,

3-β-naphthyl-5-methyl-4-isoxazole-4-carbonyl chloride,

3-phenyl-5-ethyl-4-isoxazole-4-carbonyl chloride,

3-p-chlorophenyl-5-ethyl-4-isoxazole-4-carbonyl chloride,

3-phenyl-5-isopropyl-4-isoxazole-4-carbonyl chloride,

3-phenyl-5-methylmercapto-4-isoxazole-4-carbonyl chloride,

3-methyl-5-o-chlorophenyl-4-isoxazole-4-carbonyl chloride,

3-methyl-5-p-bromophenyl-4-isoxazole-4-carbonyl chloride,

3-methyl-5-o-iodophenyl-4-isoxazole-4-carbonyl chloride,

3-methyl-5-(2,4-dichlorophenyl)-4-isoxazole-4-carbonyl chloride,

3-methyl-5-m-nitrophenyl-4-isoxazole-4-carbonyl chloride,

3-methyl-5-p-tolyl-4-isoxazole-4-carbonyl chloride,

3-methyl-5-p-nitrophenyl-4-isoxazole-4-carbonyl chloride,

3-methyl-5-p-methoxyphenyl-4-isoxazole-4-carbonyl chloride,

3-methyl-5-p-ethoxyphenyl-4-isoxazole-4-carbonyl chloride,

3-methyl-5-(2,6-dimethoxyphenyl)-4-isoxazole-4-carbonyl chloride,

3-methyl-5-p-methylsulfonylphenyl-4-isoxazole-4-carbonyl chloride,

3-methyl-5-p-fluorophenyl-4-isoxazole-4-carbonyl chloride,

3-methyl-5-p-cyanophenyl-4-isoxazole-4-carbonyl chloride,

3-methyl-5-p-methylmercaptophenyl-4-isoxazole-4-carbonyl chloride,

3-methyl-5-p-dimethylaminophenyl-4-isoxazole-4-carbonyl chloride,

3-methyl-5-α-naphthyl-4-isoxazole-4-carbonyl chloride,

3-methyl-5-β-naphthyl-4-isoxazole-4-carbonyl chloride,

3-ethyl-5-phenyl-4-isoxazole-4-carbonyl chloride,

3-ethyl-5-p-chlorophenyl-4-isoxazole-4-carbonyl chloride,

3-isopropyl-5-phenyl-4-isoxazole-4-carbonyl chloride,

3-tert. butyl-5-methyl-4-isoxazole-4-carbonyl chloride,

3-methyl-5-p-trifluoromethylphenyl-4-isoxazole-4-carbonyl chloride,

3-methyl-5-cyclohexyl-4-isoxazole-4-carbonyl chloride,

3-cyclohexyl-5-methyl-4-isoxazole-4-carbonyl chloride,

3-α-furyl-5-methyl-4-isoxazole-4-carbonyl chloride, and

3-α-thienyl-5-methyl-4-isoxazole-4-carbonyl chloride, the productsobtained are

6-(3-m-chlorophenyl-5-methyl-4-isoxazoyl-amino)-6-methylpenicillanicacid,

6-(3-(2,4-dichlorophenyl)-5-methyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-(3,4-dichlorophenyl)-5-methyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-p-tolyl-5-methyl-4-isoxazolyl-amino)-6-methylpenicillanic acid,

6-(3-o-nitrophenyl-5-methyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-m-nitrophenyl-5-methyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-p-nitrophenyl-5-methyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-p-bromophenyl-5-methyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-p-fluorophenyl-5-methyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-p-methylsulfonylphenyl-5-methyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-p-methoxyphenyl-5-methyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-p-trifluoromethylphenyl-5-methyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-o-methoxyphenyl-5-methyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-p-ethoxyphenyl-5-methyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-(3,4-dimethoxyphenyl)-5-methyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-p-dimethylaminophenyl-5-methyl-4-isoxazolyl-amino)-6-metnylpenicillanicacid,

6-(3-α-naphthyl-5-methyl-4-isoxazolyl-amino)-6-methylpenicillanic acid,

6-(3-β-naphthyl-5-methyl-4-isoxazolyl-amino)-6-methylpenicillanic acid,

6-(3-phenyl-5-ethyl-4-isoxazolyl-amino)-6-methylpenicillanic acid,

6-(3-p-chlorophenyl-5-ethyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-phenyl-5-isopropyl-4-isoxazolyl-amino)-6-methylpenicillanic acid,

6-(3-phenyl-5-methylmercapto-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-methyl-5-o-chlorophenyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-methyl-5-p-bromophenyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-methyl-5-o-iodophenyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-methyl-5-(2,4-dichlorophenyl)-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-methyl-5-m-nitrophenyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-methyl-5-p-tolyl-4-isoxazolyl-amino)-6-methylpenicillanic acid,

6-(3-methyl-5-p-nitrophenyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-methyl-5-p-methoxyphenyl-4-isoxazolyl-amino)-5-methylpenicillanicacid,

6-(3-methyl-5-p-ethoxyphenyl-4-isoxazolyl-6-methylpenicillanic acid,

6-(3-methyl-5-(2,6-dimethoxyphenyl)-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-methyl-5-p-methylsulfonylphenyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-methyl-5-p-fluorophenyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-methyl-5-p-cyanophenyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-methyl-p-methylmercaptophenyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-methyl-5-p-dimethylaminophenyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-methyl-5-α-naphthyl-4-isoxazolyl-amino)-6-methylpenicillanic acid,

6-(3-methyl-5-β-naphthyl-4-isoxazolyl-amino)-6-methylpenicillanic acid,

6-(3-ethyl-5-phenyl-4-isoxazolyl-amino)-6-methylpenicillanic acid,

6-(3-ethyl-5-p-chlorophenyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-isopropyl-5-phenyl-4-isoxazolyl-amino)-6-methylpenicillanic acid,

6-(3-tert. butyl-5-methyl-4-isoxazolyl-amino)-6-methylpenicillanic acid,

6-(3-methyl-5-p-trifluoromethylphenyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-methyl-5-cyclohexyl-4-isoxazolyl-amino)-6-methylpenicillanic acid,

6-(3-cyclohexyl-5-methyl-4-isoxazolyl-amino)-6-methylpenicillanic acid,

6-(3-α-furyl-5-methyl-4-isoxazolyl-amino)-6-methylpenicillanic acid,

6-(3-α-thienyl-5-methyl-4-isoxazolyl-amino)-6-methylpenicillanic acid,respectively.

EXAMPLES 244 - 258

By following the procedure of Example 18b and substituting an equivalentamount of the following acid chloride:

3,5-diphenyl-4-isoxazole-4-carbonyl chloride,

3-methyl-5-phenyl-4-isoxazole-4-carbonyl chloride,

3,5-dimethyl-4-isoxazole-4-carbonyl chloride,

5-benzyl-3-methyl-4-isoxazole-4-carbonyl chloride,

3-methyl-5-styryl-4-isoxazole-4-carbonyl chloride,

5-tert. butyl-3-phenyl-4-isoazole-4-carbonyl chloride,

5-(2-furyl)-3-methyl-4-isoxazole-4-carbonyl chloride,

3-methyl-5-(3',5'-dimethyl-4'-isoxazolyl)-4-isoxazole-4-carbonylchloride,

3-methyl-5-(2-thienyl)-4-isoxazole-4-carbonyl chloride,

3-(p-chlorophenyl)-5-methyl-4-isoxazole-4-carbonyl chloride,

3-methyl-5-methylmercapto-4-isoxazole-4-carbonyl chloride,

5-(p-chlorophenyl)-3-methyl-4-carbonyl chloride,

3-methyl-5-(o-nitrophenyl)-4-isoxazole-4-isoxazole-4-carbonyl chloride,

5-isopropyl-3-methyl-4-isoxazole-4-carbonyl chloride, and

5-methyl-3-(p-chlorophenyl)-4-isoxazole-4-carbonyl chloride, theproducts obtained are:

6-(3,5-diphenyl-4-isoxazolyl-amino)-6-methylpenicillanic acid,

6-(3-methyl-5-phenyl-4-isoxazolyl-amino)-6-methylpenicillanic acid,

6-(3,5-dimethyl-4-isoxazolyl-amino)-6-methylpenicillanic acid,

6-(5-benzyl-3-methyl-4-isoxazolyl-amino)-6-methylpenicillanic acid,

6-(3-methyl-5-styryl-4-isoxazolyl-amino)-6-methylpenicillanic acid,

6-(5-tert. butyl-3-phenyl-4-isoxazolyl-amino)-6-methylpenicillanic acid,

6-(5-(2-furyl)-3-methyl-4-isoxazolyl-amino)-6-methylpenicillanic acid,

6-(3-methyl-5-(3',5'-dimethyl-4'-isoxazolyl)-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-methyl-5-(2-thienyl)-4-isoxazolyl-amino)-6-methylpenicillanic acid,

6-(3-p-chlorophenyl)-5-methyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-methyl-5-methylmercapto-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(5-p-chlorophenyl)-3-methyl-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(3-methyl-5-(o-nitrophenyl)-4-isoxazolyl-amino)-6-methylpenicillanicacid,

6-(5-isopropyl-3-methyl-4-isoxazolyl-amino)-6-methylpenicillanic acid,and

6-(3-methyl-3-(p-chlorophenyl)-4-isoxazolyl-amino)-6-methylpenicillanicacid, respectively.

EXAMPLE 259

To 100 ml. aqueous solution (pH 8.0) of 10 g. crude6-amino-6-methylpenicillanic acid are added 8 g. freshly distilledphenylacetaldehyde. After 2 hours agitation at room temperature, 250 ml.of methyl cyclohexanone are added and the pH adjusted to 4.0 with HCl.After 30 minutes the phases are separated and the rich organic solventis dried by azeotropic distillation of the water present. Thetriethylamine salt is prepared by the addition of 6.5 ml of amine.

The solution is cooled to 0° - 5° and a mixture of 9.5 g.D(-)-2-phenylglycyl chloride hydrochloride in 100 ml. of methylcyclohexanone is added over a period of 1 hour, maintaining a pH of 0° -5° C. After an additional hour agitation, 100 ml. cold phosphate bufferat pH 7.5 is added and the pH adjusted to 2.0. The solvent layer isdiscarded and the aqueous layer adjusted to pH 5.0. After 1 hour,filtration and drying yields 6-methyl-ampicillin.

By substituting the reaction product of sodium D(-)-α-aminophenylacetate with methyl acetoacetate for the D(-)-2-phenylglycyl chloridehydrochloride in the foregoing procedure, 6-methyl-ampicillin is alsoproduced.

EXAMPLES 260 - 269

In the procedure of Example 259, the D-(-)-2-phenylglycyl chloride isreplaced with an equimolar amount of

α-(1-naphthyl)glycyl chloride,

α-(2-naphthyl)glycyl chloride,

α-(1-chloro-2-naphthyl)glycyl chloride,

α-(2-methyl-7-naphthyl)glycyl chloride,

α-(6-nitro-1-naphthyl)glycyl chloride,

α-(2,7-dibromo-3-naphthyl)glycyl chloride,

α-(4-trifluoromethyl-1-naphthyl)glycyl chloride

α-(8-iodo-1-naphthyl)glycyl chloride,

α-(1-methoxy-2-naphthyl)glycyl chloride, and

α-(4-acetamido-1-naphthyl)glycyl chloride, respectively, to produce

6-[α-amino-(1-naphthyl)acetamido]-6-methylpenicillanic acid,

6-[α-amino-(2-naphthyl)acetamido]-6-methylpenicillanic acid,

6-[α-amino-(1-chloro-2-naphthyl)acetamido]-6-methylpenicillanic acid,

6-[α-amino-(2-methyl-7-naphthyl)acetamido]-6-methylpenicillanic acid,

6-[α-amino-(6-nitro-1-naphthyl)acetamido]-6-methylpenicillanic acid,

6-[α-amino-(2,7-dibromo-3-naphthyl)acetamido]-6-methylpenicillanic acid,

6-[α-amino-(4-trifluoromethyl-1-naphthyl)acetamido]-6-methylpenicillanicacid,

6-[α-amino-(8-iodo-1-naphthyl)acetamido]-6-methylpenicillanic acid,

6-[α-amino-(1-methoxy-2-naphthyl)acetamido]-6-methylpenicillanic acid,and

6-[α-amino-(4-acetamido-1-naphthyl)acetamido]-6-methylpenicillanic acid,respectively.

EXAMPLE 270

10 g. triethylamine salt of 6-amino-6-methylpenicillanic acid isdissolved in 100 ml. methylene chloride. The solution is cooled to 0° -5° and 7 g. 2,6-dimethoxy benzoyl chloride is added dropwise over aperiod of 11/2 hours, maintaining the same temperature. After anadditional 30 minutes, the solution is mixed with an equal volume ofcold (5° - 10°) phosphate buffer (pH 7.5). To complete the hydrolysis ofthe intermediate, the pH is adjusted to pH 2.0 and the mixture isagitated for 15 minutes. The aqueous layer is discarded and the acidorganic solvent layer is mixed with 50 ml. of cold water and neutralizedto pH 7.5 with 20% sodium hydroxide. The aqueous solution is separatedand concentrated into 100 ml. methyl isobutylketone. After standingovernight in the cold room, the crystals are filtered and dried to yield6-methyl-methicillin.

EXAMPLES 271 - 277

In the procedure of Example 270, the phenoxyacetyl chloride is replacedby an equimolar amount of thiophene-2-carboxylic acid chloride,

thiophene-3-carboxylic acid chloride,

furan-2-carboxylic acid chloride,

furan-3-carboxylic acid chloride,

isonicotinyl chloride,

pyrrolidinecarboxylic acid chloride, and

N-methylpiperidine-3-carboxylic acid chloride,

respectively, to produce the sodium salt of

6-(2-thiophene)carboxamidopenicillanic acid,

6-(3-thiophene)carboxamidopenicillanic acid,

6-(2-furan)carboxamidopenicillanic acid,

6-(3-furan)carboxamidopenicillanic acid,

6-isonicotinylcarboxamidopenicillanic acid,

6-pyrrolidinecarboxamidopenicillanic acid, and

6-[3-(N-methylpiperidine)]carboxamidopenicillanic acid, respectively.

EXAMPLE 278 6-Amino-6-allylpenicillanic acid

Following the procedure of Example 10, but utilizing allyl chloride inlieu of methyl chloride, the desired product is recovered.

Example 279 6-Amino-6-cyclohexylpenicillanic acid

Utilizing the procedure of Example 10, but substituting cyclohexylchloride in lieu of methyl chloride, the desired product is recovered.

Example 280 N-Benzylidene-6-amino-6-allylpenicillanic acid, methyl ester

Following the procedure of Example 11, but utilizing an equivalentamount of allyl chloride in lieu of methyl iodide, the desired productis recovered.

Example 281 6-Phenylacetamido-6-benzylpenicillanic acid

Utilizing the procedure of Example 18, but substituting benzyl chloridefor methyl iodide, the desired product is recovered.

Examples 282 - 284

By following the procedure of Example 11, and substituting in place ofthe N-benzylidene-6-aminopenicillanic acid methyl ester an equivalentamount of:

N-(o-nitrobenzylidene)-6-aminopenicillanic acid,

N-(phenylethylidene)-6-aminopenicillanic acid, and

N-ethylidene-6-aminopenicillanic acid, and an additional equivalent ofsodium hydride the products obtained are:

N-(o-nitrobenzylidene)-6-amino-6-methyl-penicillanic acid,

N-(phenethylidene)-6-amino-6-methyl-penicillanic acid, and

N-(ethylidene)-6-amino-6-methyl-penicillanic acid.

What is claimed is:
 1. A compound of the formula ##STR7## wherein R³ isselected from the group consisting of lower alkyl, allyl and benzyl; Xis selected from the group consisting of hydrogen, halogen, lower alkyl,lower alkoxy, hydroxy, nitro, and amino; and R⁴ is selected from thegroup consisting of hydrogen, lower alkyl, benzyl, diphenylmethyl,trichloroethyl and trimethylsilyl; and pharmaceutically acceptable saltsthereof.
 2. The compound of claim 1 wherein R³ is lower alkyl.
 3. Thecompound of claim 2 wherein R³ is methyl, X is hydrogen, and R⁴ ismethyl.
 4. The compound of claim 2 wherein R³ is methyl; X is hydrogen;and R⁴ is benzyl.
 5. The compound of claim 2 wherein R³ is methyl; X ishydrogen; and R⁴ is diphenylmethyl.